The present invention relates to a process for preparing a xcex2-hydroxyester.
The xcex2-hydroxyester of the present invention has an active hydroxyl group in the xcex2-position, and is a very important compound in terms of synthetic chemistry. For example, 3-hydroxycepham compound, which can be readily converted to 3-norcephem skeleton, is an important intermediate of ceftizoxime or ceftibutene both widely used as an injection and an oral drug, respectively (Katsuji SAKAI, xe2x80x9cHandbook of Latest Antibioticsxe2x80x9d, 9th ed., pp. 72 and 85, 1994) and is in industrially wide use.
A xcex2-keto ester is generally unstable under reaction conditions under which hydrolysis tends to occur such as alkaline conditions. The reduction of xcex2-keto ester under such conditions involves various side reactions, thus making it difficult to give the contemplated product.
For example, a 3-ketocepham compound (3-hydroxycephem compound) is unstable under such reaction conditions and, when reacted, gives a reaction product in low yields, so that the reaction should be conducted at an extremely low temperature. Stated more specifically, known methods include those described in JP-B-59-34714 and Pure and Appl. Chem., 59, 1041 (1987) (hereinafter referred to as xe2x80x9cPublication 1xe2x80x9d). JP-B-59-34714 discloses a method wherein the reaction is carried out in methanol at 0xc2x0 C. The reproduced method shows that a product is produced in a yield of only 50 to 60%. On the other hand, Publication 1 discloses a method wherein a 3-hydroxycephem compound is dissolved in a solvent mixture of dichloromethane and methanol and the solution is reduced at xe2x88x9260xc2x0 C. using sodium borohydride. Since the reaction is performed at a low temperature of xe2x88x9260xc2x0 C., the method is not industrially advantageous.
Publication 1 states that when the reduction is conducted at 0xc2x0 C., i.e. a temperature commonly employed, a reaction for removal of substituent R3 occurs, resulting in production of the contemplated product in a very low yield. The method of JP-B-59-34714 produces a product in a low yield presumably for the same reason.
Helvetica Chimica Acta 57, 1919 (1974) (hereinafter referred to as xe2x80x9cPublication 2xe2x80x9d) discloses a method in which exomethylene cepham is subjected to ozone decomposition as illustrated below in a scheme, giving a 3-hydroxycephem compound, while ozonide is simultaneously reduced in the same reaction system to produce a 3-hydroxycepham compound. However, the yield of the product is as low as 31.8% which means that the method is not suitable for practical use. 
wherein R is benzyl group.
As described above, a practical process has not been established for preparing a xcex2-hydroxyester from a xcex2-keto ester of low stability. Currently there is an urgent need for developing an industrially practical process.
An object of the present invention is to provide a process widely applicable for preparing a xcex2-hydroxyester, the process being free from the drawbacks of conventional processes and capable of giving the contemplated xcex2-hydroxyester in a high yield and with a high purity.
The present invention provides a process for preparing a xcex2-hydroxyester comprising reducing a xcex2-keto ester in the presence of a salt of ammonium borohydride.
In an attempt to develop the process for preparing a xcex2-hydroxyester, the present inventor directed attention to the fact that the xcex2-hydroxyester or xcex2-keto ester shows a very unstable behavior in reduction under alkaline conditions.
It is known that reduction at a relatively high temperature (e.g. approximately 0xc2x0 C.) entails side reactions such as hydrolysis, thus giving the contemplated compound in a lower yield and with a lower purity. For example, the reaction of Publication 1 produces (C6H5)2CHOH as a by-product. Publication 1 explains that the by-product is produced due to the attack by hydride when the reaction temperature is elevated to approximately 0xc2x0 C.
Considering that the by-product is produced due to a high basicity derived from sodium borohydride or due to a great hydride-reducing capability of sodium borohydride, the present inventor attempted to find out a salt of borohydride which does not increase the basicity in the reaction system and which is capable of selectively reducing a xcex2-keto ester or its ketoenol isomer.
It is already known to produce a salt of borohydride such as aluminum, lithium or zinc salt in the reaction system for use in the reduction. However, such salt failed to achieve the contemplated object. On the other hand, a salt of ammonium borohydride has not been heretofore used for this purpose and was proposed as a useful reagent for the first time in this invention. It was discovered that the foregoing reduction advantageously proceeds in the presence of a salt of ammonium borohydride, giving the contemplated xcex2-hydroxyester in a high yield and with a high purity. Further, no by-product was produced even when the reaction temperature was raised to 0xc2x0 C.
In the present invention, a xcex2-hydroxyester is prepared by reduction of xcex2-keto ester in the presence of a salt of ammonium borohydride.
The xcex2-keto ester for use as the starting material in the process of the present invention is not limited and includes conventional compounds. Among useful xcex2-keto esters, preferred are 3-keto cepham compound represented by the formula (1) and 3-hydroxycephem compound represented by the formula (1xe2x80x2) which is the keto-enol isomer of the 3-keto cepham compound 
wherein R1 is hydrogen atom, halogen atom, amino group, protected amino group or a group xe2x80x94Nxe2x95x90CHxe2x80x94Ar (in which Ar is phenyl group optionally having a substituent), R2 is lower alkyl group optionally having hydroxyl group or protected hydroxyl group as a substituent, hydrogen atom, halogen atom, lower alkoxy group, lower acyl group, hydroxyl group or protected hydroxyl group, and R3 is hydrogen atom or carboxylic acid-protecting group 
wherein R1, R2 and R3 are as defined above.
Examples of the groups described in the present specification are as follows unless they are otherwise specified:
Halogen atom means fluorine, chlorine, bromine, iodine, or the like. Lower alkyl group means, for example, a straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of the lower alkoxy groups are straight-chain or branched alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
Examples of the protected amino group represented by R1 are phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, phenylacetoxyacetamido, xcex1-oxophenylacetamido, thienylacetamido, benzamido, p-methylbenzamido, p-t-butylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, etc. In addition to these, there are the groups disclosed in xe2x80x9cProtective Groups in Organic Synthesis written by Theodora W. Greene, 1981, by John Wiley and Sons. Inc.xe2x80x9d (hereinafter referred to as the xe2x80x9cPublication 3xe2x80x9d), Chap. 7 (pp. 218-287), and phenylglycylamido, phenylglycylamido in which amino group is protected, p-hydroxyphenylglycylamido, and p-hydroxyphenylglycylamido in which either of amino and hydroxyl, or both of these are protected. Examples of protective groups for the amino of phenylglycylamido group and p-hydroxyphenylglycylamido group are those disclosed in the Publication 3, Chap. 7 (pp. 218-287). Examples of protective groups for the hydroxyl of p-hydroxyphenylglycylamido are those disclosed in the Publication 3, Chap. 2 (pp. 10-72).
Examples of phenyl groups represented by Ar in xe2x80x94Nxe2x95x90CHxe2x80x94Ar group defined by R1 are phenyl and phenyl groups such as p-methoxyphenyl, p-nitrophenyl and m-hydroxyphenyl which may have a substituent including lower alkoxyl group, nitro, hydroxyl or the like.
Examples of the lower acyl represented by R2 are straight-chain or branched acyl groups having 1 to 4 carbon atoms such as formyl, acetyl, propionyl, butyryl and isobutyryl.
Examples of protected hydroxyl groups for lower alkyl represented by R2 and substituted with hydroxyl group or protected hydroxyl group, and examples of protective groups for the protected hydroxyl represented by R2, are those disclosed in the Publication 3, Chap. 2 (pp. 10-72). The above lower alkyl groups represented by R2 is substituted by substituents of the same or different kinds selected from among hydroxyl group and the protected hydroxyl groups as defined above, and at least one of such substituents may be substituted in the same or different carbon.
Exemplary of the carboxylic acid protecting groups represented by R3 are benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloroethyl, tert-butyl, or the groups described in the Publication 3, Chap. 5 (pp. 152-192).
3-Keto cepham compound (1) and its keto-enol isomer (1xe2x80x2) can be prepared according to the method disclosed in the Publication 1 as shown in the reaction scheme below. In the scheme, Me stands for methyl, Ph for phenyl, Ts for tosyl and Py for pyridyl. 
When 3-keto cepham compound (1) or its keto-enol isomer (1xe2x80x2) is used as the starting material in the present invention, 3-hydroxycepham compound represented by the formula (2) can be prepared in a high yield and with a high purity 
wherein R1, R2 and R3 are as defined above.
The salt of ammonium borohydride for use in the present invention includes not only ammonium borohydride but tetramethylammonium borohydride, tetraethylammonium borohydride, tetra-n-propylammonium borohydride, tetra-n-butylammonium borohydride and like tetraalkylammonium borohydrides. The amount of a salt of ammonium borohydride to be used in the invention is not specifically limited and is such that the xcex2-keto ester used as the starting material is completely exhausted. The amount is usually about 1 to about 10 moles, preferably about 1 to about 3 moles, per mole of xcex2-keto ester used.
In the present invention, it is possible to use a salt of ammonium borohydride prepared in the reaction system. The salt of ammonium borohydride can be produced by the presence of alkali metal salt of borohydride and ammonium salt in the reaction system. Examples of alkali metal salts of borohydride are sodium borohydride and potassium borohydride. The alkali metal salts of borohydride can be used either alone or in combination. The amount of alkali metal salt of borohydride to be used in the invention is not specifically limited and is such that the xcex2-keto ester used as the starting material is completely exhausted due to the salt of ammonium borohydride produced by the reaction of alkali metal salt of borohydride with ammonium salt. The amount is usually about 1 to about 10 moles, preferably about 1 to about 3 moles, per mole of xcex2-keto ester used.
Useful ammonium salts are, for example, ammonium chloride, ammonium bromide, ammonium iodide, tetraethylammonium chloride, tetrabutylammonium bromide and like halogenated ammonium salts, ammonium perchlorate, tetraethylammonium perchlorate, tetrabutylammonium perchlorate and like salts of ammonium perchlorate, tetrabutylammonium tosylate and like salts of ammonium sulfonate, tetraethylammonium borofluoride, tetrabutylammonium borofluoride and like salts of ammonium borofluorides. Among them, halogenated ammonium salts are preferably usable. Ammonium salts can be used either alone or in combination. The amount of ammonium salt to be used is not specifically limited and can be suitably selected from a wide range. The amount is usually about 0.01 to about 5 kg, preferably about 0.1 to about 2 kg, per kilogram of xcex2-keto ester used.
The reduction of the present invention is usually carried out in a solvent. Useful solvents are, for example, methanol, ethanol, propanol, n-butanol and like straight-chain lower alkyl alcohols, 2-propanol, 2-butanol, tert-butanol and like branched-chain lower alkyl alcohols, ethylene glycol, propylene glycol and like dihydric alcohols, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, diglyme, triglyme and like ethers, tetrahydrofuran, dioxane, dioxolan and like cyclic ethers, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile and like nitriles, benzene, toluene, xylene, chlorobenzene, anisole and like substituted or unsubstituted aromatic hydrocarbons, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride and like halogenated hydrocarbons, pentane, hexane, heptane, octane and like aliphatic hydrocarbons, cyclopentane, cyclohexane, cycloheptane, cyclooctane and like cycloalkanes.
These solvents can be used either alone or in combination. Among them, preferred solvents are straight-chain lower alkyl alcohols and solvent mixtures of such alcohols and other solvents. These solvents may contain water, when so required. The amount of the solvent to be used is not specifically limited but is usually about 2 to about 200 liters, preferably about 5 to about 50 liters, per kilogram of xcex2-keto ester used.
The reaction according to the invention is conducted at a temperature of about xe2x88x9278 to about +150xc2x0 C., preferably about xe2x88x9230 to about +50xc2x0 C. and is completed at the same time as the completion of mixing of starting compounds or about 10 hours or less after mixing.
When the obtained product is an unstable compound in the present invention, it is possible, when required, to inactivate the salt of ammonium borohydride remaining in the reaction system after completion of the reaction. The inactivation can be done by addition of an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid to the reaction system.
The desired product obtained by the reaction of the invention, i.e. 3-hdroxycepham compound, can be easily isolated and purified from the reaction system by conventional means.